What is the preferred antiviral regimen for a treatment‑naïve patient with chronic hepatitis C and chronic kidney disease (elevated serum creatinine)?

Treatment of Hepatitis C in Patients with Elevated Creatinine

For treatment-naïve patients with chronic hepatitis C and chronic kidney disease, the preferred regimen depends on the degree of renal impairment: use any licensed pangenotypic DAA for eGFR ≥30 mL/min/1.73 m², but switch to glecaprevir-pibrentasvir or grazoprevir-elbasvir for eGFR <30 mL/min/1.73 m² or dialysis patients. 1

Treatment Algorithm Based on Kidney Function

For CKD Stage 1-3b (eGFR ≥30 mL/min/1.73 m²)

• Any licensed DAA regimen can be used without dose adjustment, including sofosbuvir-based combinations such as sofosbuvir-velpatasvir, ledipasvir-sofosbuvir, glecaprevir-pibrentasvir, or grazoprevir-elbasvir. 1
• The FDA has recently indicated that sofosbuvir-velpatasvir requires no dose adjustments even in patients with CKD including those on dialysis, though this was not formally reviewed in the original KDIGO guideline. 1
• Treatment duration is typically 12 weeks for most patients, with adjustments based on genotype, cirrhosis status, and prior treatment history. 1

For CKD Stage 4-5 (eGFR <30 mL/min/1.73 m²) Including Dialysis

First-line pangenotypic option:

• Glecaprevir-pibrentasvir 300/120 mg daily for 8-12 weeks is the preferred pangenotypic regimen, achieving 98% SVR in the EXPEDITION-4 trial with excellent tolerability across all genotypes. 1
• This regimen is metabolized hepatically with minimal renal elimination, requires no dose adjustment, and can be used in patients with compensated cirrhosis. 1

Genotype-specific alternative:

• Grazoprevir-elbasvir 100/50 mg daily for 12 weeks for genotypes 1a, 1b, and 4 only, achieving 99% SVR in the C-SURFER trial with CKD stage 4-5 patients including those on hemodialysis. 1, 2
• Both drugs are >90% excreted in feces with <1% renal elimination, making dose adjustment unnecessary. 1

Other options with high-quality evidence:

• Sofosbuvir-daclatasvir for 12-24 weeks (all genotypes, high-quality evidence with 571 patients). 1
• Sofosbuvir-velpatasvir for 12 weeks (all genotypes, high-quality evidence with 405 patients in dialysis population). 1

For Dialysis Patients (CKD Stage 5D)

• Timing of administration does not need to be altered on dialysis days because DAAs are highly protein-bound and not significantly removed by dialysis. 1
• The same regimens recommended for CKD stage 4-5 apply to dialysis patients. 1
• Sofosbuvir-velpatasvir and glecaprevir-pibrentasvir have the highest quality evidence in the dialysis population specifically. 1

Critical Pre-Treatment Assessment

Mandatory screening and monitoring:

• Test all patients for hepatitis B virus (HBsAg, anti-HBc, anti-HBs) before initiating DAA therapy to prevent HBV reactivation. 1
• If HBsAg is positive, initiate concurrent HBV nucleoside/nucleotide analogue therapy. 1
• If only anti-HBc is positive (resolved infection), monitor HBV DNA and liver function tests during DAA therapy. 1

Drug-drug interaction assessment:

• Perform comprehensive drug-drug interaction screening before treatment, particularly in kidney transplant recipients on immunosuppressants. 1
• Grazoprevir-elbasvir interactions to avoid: CYP3A4 inducers (rifampin, phenytoin, St. John's wort) are contraindicated; OATP1B1/3 inhibitors (enalapril, statins, digoxin, some ARBs) may increase grazoprevir levels and cause hyperbilirubinemia. 1
• Monitor calcineurin inhibitor levels (tacrolimus, cyclosporine) during and after DAA treatment in kidney transplant recipients, as levels may fluctuate significantly. 1

Special Populations

Kidney Transplant Recipients

• Sofosbuvir-ledipasvir or sofosbuvir-daclatasvir for 12-24 weeks have the highest quality evidence (300 and 290 patients respectively) in transplant recipients with eGFR ≥30 mL/min/1.73 m². 1
• For transplant recipients with eGFR <30 mL/min/1.73 m², use the same regimens as CKD stage 4-5 non-transplant patients. 1
• More than half of kidney transplant recipients require dose adjustment of immunosuppressive medications during DAA therapy. 1
• Glecaprevir-pibrentasvir achieved 98% SVR in the MAGELLAN-2 trial including 20 kidney transplant recipients. 1

Patients with Cirrhosis

• Grazoprevir cannot be used in Child-Turcotte-Pugh class B or C cirrhosis due to risk of hepatotoxicity. 1
• Glecaprevir-pibrentasvir can be used in compensated cirrhosis (Child-Pugh A) but is contraindicated in decompensated cirrhosis. 1
• Treatment outcomes are generally consistent between cirrhotic and non-cirrhotic patients when appropriate regimens are selected. 1

Common Pitfalls and Caveats

Sofosbuvir use in severe CKD:

• Traditional teaching states sofosbuvir is contraindicated when eGFR <30 mL/min/1.73 m² because it is 80% renally cleared and its metabolite accumulates 20-fold in severe renal impairment. 1
• However, recent meta-analysis and FDA guidance suggest sofosbuvir-based regimens may be safe and effective even in stage 4-5 CKD, with pooled SVR of 97.1% and serious adverse event rate of 4.8%. 3
• One study reported high rates of acute kidney injury (AKI) in stage 4 CKD patients treated with ombitasvir-paritaprevir-ritonavir, recommending that stage 4 patients wait until starting hemodialysis or transplantation before treatment. 4
• The safest approach for eGFR <30 mL/min/1.73 m² remains glecaprevir-pibrentasvir or grazoprevir-elbasvir, which have extensive safety data and no renal elimination. 1

Monitoring during treatment:

• Monitor serum creatinine and eGFR regularly during DAA therapy, as some studies report deterioration of kidney function in 14% of patients. 5
• Anemia is the most common adverse event (occurring in up to 40% of patients), particularly when ribavirin is added, and may require blood transfusions. 5
• Viral eradication may improve hepatic metabolic function, potentially altering levels of concomitant medications with narrow therapeutic indices (e.g., cyclosporine, warfarin). 1

Treatment candidacy:

• Little evidence supports initiating HCV treatment in patients with limited life expectancy (<12 months), though this decision should be individualized. 1
• Treat kidney transplant candidates in collaboration with the transplant center to optimize timing, as achieving SVR pre-transplant improves outcomes. 1

Treatment Outcomes

• Overall SVR rates exceed 90-95% across all CKD stages with modern DAA regimens. 1
• Achieving SVR reduces liver-related mortality, cardiovascular mortality, and improves quality of life in CKD and dialysis patients. 1, 6
• SVR rates are consistent regardless of cirrhosis status, prior treatment history, or dialysis status when appropriate regimens are selected. 1, 2